Transferrin with plutonium in its C lobe and iron in its N lobe (green) has a structure close enough to that of transferrin with its usual two irons (yellow) that it can be taken up by cells. If the Pu and Fe are reversed (blue), the transferrin receptor doesn’t recognize or admit transferrin.

Credit: Nat. Chem. Biol.

Transferrin with plutonium in its C lobe and iron in its N lobe (green) has a structure close enough to that of transferrin with its usual two irons (yellow) that it can be taken up by cells. If the Pu and Fe are reversed (blue), the transferrin receptor doesn’t recognize or admit transferrin.

Credit: Nat. Chem. Biol.

Plutonium gets inside cells by hitching a ride on the iron-transport protein transferrin—but only when iron comes along for the ride, scientists at Argonne National Laboratory and Northwestern University report (Nat. Chem. Biol., DOI: 10.1038/nchembio.594). This is the first time a pathway for plutonium uptake has been found, and it could lead to ways of preventing plutonium poisoning.

Scientists have known since the 1960s that transferrin can bind plutonium as well as iron, but they didn’t think plutonium could enter cells that way because the transferrin receptor on cell surfaces wouldn’t recognize the plutonium-laden protein. It turns out that’s only partially true. Using small-angle X-ray scattering, the team, led by Argonne scientist Mark P. Jensen, has shown that transferrin receptors can recognize certain plutonium-toting transferrins.

Transferrin has two metal-binding sites, one each in the so-called N and C lobes. Only plutonium-bound forms of transferrin that contain plutonium in the C lobe and iron in the N lobe can get into cells. If the two metals are swapped or if both lobes contain plutonium, the N lobe doesn’t close properly, and the receptor can’t recognize the protein.

“The surprising thing about our work is that, in half of the molecule, if the plutonium goes in there, transferrin treats it just like it’s iron,” Jensen says. “If it goes into the other half of the molecule, the transferrin says: ‘Hey, wait a minute, you’re not iron. Even though you’re bound here, I’m not going to respond to you the same way I respond to iron.’ ”

The researchers also showed that treatment with the antimalarial drug chloroquine, which is known to block iron uptake, stops plutonium uptake. The use of such a drug as a treatment for plutonium poisoning is a “long way down the road,” Jensen is quick to caution.

There appear to be other pathways that let plutonium into cells, Jensen says, but those pathways aren’t yet known.

Commenting on the work, Chuan He, a chemist who studies metal recognition by proteins at the University of Chicago, says: “It will be interesting to explore the underlying mechanism and investigate potential biological functions of this behavior. This work also presents a pathway that can be potentially inhibited with small molecules to block cellular uptake of plutonium as a new strategy for future therapies against plutonium poisoning.”

Jensen and coworkers have other plans for the transferrin system. They hope to exploit the system to separate metal ions.